Epithelial-mesenchymal transition as a mechanism for the progression of breast carcinoma

Epithelial-mesenchymal transition (EMT) is a major process controlling multiple events during development. EMT has been conserved throughout evolution to control morphogenetic events, such as the formation of the three primary germ layers during gastrulation. Most interestingly, signal transduction pathways have been remarkably conserved in many different species. EMT pathways are also tightly connected to determination and differentiation programmes, and are reactivated in adult tissues following injury or exposure to toxic agents. EMT is likely to operate during the early stages of carcinoma invasion that lead to blood or lymph vessel intravasation. Mesenchymal-like carcinoma cells undergo a mesenchymal-to-epithelial transition in distant sites from the primary tumour and eventually become micrometastatic. We have characterised bone marrow micrometastases from breast cancer patients and found that the detection of micrometastatic carcinoma cells was associated with poorer distant metastasis-free survival, local relapse-free survival, and overall survival. Despite high rates of adjuvant systemic treatment and breast irradiation in this series, disseminated carcinoma cells remain a prognostic factor, in favour of the resistance to treatment of locally or distant disseminated cancer cells in bone marrow-positive patients. In addition, we detected micrometastatic carcinoma cells in patients with T1 tumours, suggesting that dissemination occurs much earlier during tumour progression than is generally accepted. Thus, bone marrow micrometastases should become a very useful prognostic indicator for relapse, and an excellent surrogate marker for patient's response to treatment. The mesenchymal-like state of carcinoma confers stemness, protection from cell death, escape from immune response and, most importantly, resistance to conventional and targeted therapies. Current strategies based on the EMT concept are aimed at designing new therapeutic approaches that interfere with the plasticity of carcinoma cells. Our laboratory has devised a high-content, high-throughput screen for EMT. Several combinations of drugs have been shown to selectively inhibit EMT. This strategy may be used to interfere with tumour progression, particularly in breast carcinomas that have acquired resistance to conventional therapies.